5′-Methylthioadenosine phosphorylase (MTAP) functions in the polyamine biosynthesis pathway, in purine salvage in mammals. It catalyses the reversible phosphorolysis of 5′-methylthioadenosine (MTA) to adenine and 5-methylthio-α-D-ribose-1-phosphate (MTR-1P). The adenine formed is subsequently recycled and converted into nucleotides. Essentially, the only source of free adenine in the human cell is a result of the action of these enzymes. The MTR-1P is subsequently converted into methionine by successive enzymatic actions.
MTA is a by-product of the reaction involving the transfer of an aminopropyl group from decarboxylated S-adenosyl methionine to putrescine during the formation of spermidine and spermine. The reactions are catalyzed by spermidine synthase and spermine synthase. The synthases are very sensitive to product inhibition by accumulation of MTA. Therefore, inhibition of MTAP severely limits the polyamine biosynthesis and the salvage pathway for adenine in the cells.
MTAP deficiency due to a genetic deletion has been reported with many malignancies. The loss of MTAP enzyme function in these cells is known to be due to homozygous deletions on chromosome 9 of the closely linked MTAP and p16/MTS1 tumour suppressor gene. As absence of p16/MTS1 is probably responsible for the tumour, the lack of MTAP activity is a consequence of the genetic deletion and is not causative for the cancer. However, the absence of MTAP alters the purine metabolism in these cells so that they are mainly dependent on the de novo pathway for their supply of purines. That makes these cells unusually sensitive to inhibitors like methotrexate and azaserine that block the de novo pathway. Therefore, a combination therapy of methotrexate or azaserine with an MTAP inhibitor will have unusually effective anti-tumour properties.
WO 2004/018496 describes compounds, including MTDIA, which are inhibitors of nucleoside processing enzymes. US 2010/0222370 describes that MTDIA is useful in the treatment of prostate and head and neck cancers.
It is an object of the invention to provide salt forms of (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(methylthiomethyl)pyrrolidin-3-ol, or to at least provide the public with a useful alternative.